Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome.

BACKGROUND: Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and squamous-cell carcinoma. The cause is unknown, and mortality is high. METHODS: We evaluated four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM. Genomic sequencing independently identified three heterozygous variants in a specific region of the gene that encodes signal transducer and activator of transcription 4 (STAT4). Primary skin fibroblast and cell-line assays were used to define the functional nature of the genetic defect. We also assayed gene expression using single-cell RNA sequencing of peripheral-blood mononuclear cells to identify inflammatory pathways that may be affected in DPM and that may respond to therapy. RESULTS: Genome sequencing revealed three novel heterozygous missense gain-of-function variants in STAT4. In vitro, primary skin fibroblasts showed enhanced interleukin-6 secretion, with impaired wound healing, contraction of the collagen matrix, and matrix secretion. Inhibition of Janus kinase (JAK)-STAT signaling with ruxolitinib led to improvement in the hyperinflammatory fibroblast phenotype in vitro and resolution of inflammatory markers and clinical symptoms in treated patients, without adverse effects. Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that were appropriately modified through JAK inhibition. CONCLUSIONS: Gain-of-function variants in STAT4 caused DPM in the families that we studied. The JAK inhibitor ruxolitinib attenuated the dermatologic and inflammatory phenotype in vitro and in the affected family members. (Funded by the American Academy of Allergy, Asthma, and Immunology Foundation and others.).

USP6 rearrangement in pediatric nodular fasciitis.

Nodular fasciitis (NF) is a myofibroblastic proliferation that is uncommonly present in pediatric patients. These benign neoplasms can masquerade as more insidious sarcomatous proliferations on both clinical exam and initial histopathologic review, often prompting undue concern in patients, parents, and providers. While immunohistochemical analysis of NF can be variable, adding to the diagnostic uncertainty, molecular analysis documenting ubiquitin-specific protease 6 (USP6) gene rearrangement can help confirm the diagnosis as an association between NF and USP6 overexpression was first identified 10 years ago in an analysis that found rearrangements of the involved locus in over 90% of studied samples. In this report, we review one case of NF located on the chin of a nine-year-old girl in which molecular testing was essential to secure the correct diagnosis, and provide a summary of documented cases of USP6 overexpression in transient pediatric neoplasms.

Neonatal Myocardial Infarction: A Proposed Algorithm for Coronary Arterial Thrombus Management.

BACKGROUND: Neonatal myocardial infarction is rare and is associated with a high mortality of 40% to 50%. We report our experience with neonatal myocardial infarction, including presentation, management, outcomes, and our current patient management algorithm. METHODS: We reviewed all infants admitted with a diagnosis of coronary artery thrombosis, coronary ischemia, or myocardial infarction between January 2015 and May 2021. RESULTS: We identified 21 patients (median age, 1 [interquartile range (IQR), 0.25-9.00] day; weight, 3.2 [IQR, 2.9-3.7] kg). Presentation included respiratory distress (16), shock (3), and murmur (2). Regional wall motion abnormalities by echocardiogram were a key criterion for diagnosis and were present in all 21 with varying degrees of depressed left ventricular function (severe [8], moderate [6], mild [2], and low normal [5]). Ejection fraction ranged from 20% to 54% (median, 43% [IQR, 34%-51%]). Mitral regurgitation was present in 19 (90%), left atrial dilation in 15 (71%), and pulmonary hypertension in 18 (86%). ECG was abnormal in 19 (90%). Median troponin I was 0.18 (IQR, 0.12-0.56) ng/mL. Median BNP (B-type natriuretic peptide) was 2100 (IQR, 924-2325) pg/mL. Seventeen had documented coronary thrombosis by cardiac catheterization. Seventeen (81%) were treated with intracoronary tPA (tissue-type plasminogen activator) followed by systemic heparin, AT (antithrombin), and intravenous nitroglycerin, and 4 (19%) were treated with systemic heparin, AT, and intravenous nitroglycerin alone. Nineteen of 21 recovered. One died (also had infradiaphragmatic total anomalous pulmonary venous return). One patient required a ventricular assist device and later underwent heart transplant; this patient was diagnosed late at 5 weeks of age and did not respond to tPA. Nineteen of 21 (90%) regained normal left ventricular function (ejection fraction, 60%-74%; mean, 65% [IQR, 61%-67%]) at latest follow-up (median, 6.8 [IQR, 3.58-14.72] months). Two of 21 (10%) had residual trivial mitral regurgitation. After analysis of these results, we present our current algorithm, which developed and matured over time, to manage neonatal myocardial infarction. CONCLUSIONS: We experienced a lower mortality rate for infants with neonatal infarction than that reported in the literature. We propose a post hoc algorithm that may lead to improvement in patient outcomes following coronary artery thrombus.

Congenital cutaneous non-neural granular cell tumor mimicking herpetic infection: Case report and review of the literature.

We present a case of a female neonate with a cluster of six skin colored to yellowish pseudovesicular papules on her right forearm present since birth, initially thought to be a herpes simplex virus infection. Punch biopsy with immunostaining revealed a diagnosis of S100-negative, CD163-positive congenital cutaneous non-neural granular cell tumor. Only four other reports are presented in the literature of this entity, three of which also presented on the arm with somewhat similar clinical findings. We briefly reviewed the subtypes of classic and S100-negative non-neural granular cell tumors.

Hereditary Spherocytosis as an Atypical Presentation of Anemia in Ulcerative Colitis.

Anemia is encountered in up to two-thirds of all patients with inflammatory bowel disease (IBD). We are reporting a case of a 9-year-old female with history of very early onset IBD ulcerative colitis, and primary sclerosing cholangitis who was found to have hereditary spherocytosis as the etiology of her anemia. Despite good clinical response to IBD therapy, she continued to have persistent normocytic anemia. Liver biopsy and magnetic resonance cholangiopancreatography for uptrending liver transaminases demonstrated iron deposition which led to a T2-weighted magnetic resonance imaging study that quantified significant iron deposition in her liver and kidneys. Without any history of blood transfusions, these findings were concerning for hereditary hemochromatosis, but the hereditary hemochromatosis gene test was negative. Whole genome sequencing identified a pathogenic de novo variant consistent with hereditary spherocytosis. Table of Contents Summary: A novel presentation of anemia in inflammatory bowel disease.

Acute Megakaryoblastic Leukemia with Trisomy 21 and Tetrasomy 21 Clones in a Phenotypically Normal Child with Mosaic Trisomy 21.

Pediatric acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML) that may be divided into two subgroups: (1) Down syndrome- (DS-) related AMKL which generally has a favorable prognosis and (2) non-DS-related AMKL which generally has a poorer outcome. We report a phenotypically normal child with AMKL with trisomy 21 (T21) and tetrasomy 21 clones. Subsequently, she was diagnosed with mosaic T21. She underwent reduced-intensity therapy with good outcome. We review the literature regarding AMKL-associated cytogenetic abnormalities and AMKL in association with DS. We suggest evaluation for mosaic T21 in phenotypically normal pediatric patients with T21-positive AML.

Aortopulmonary window in tetralogy of Fallot with absent conal septum.

BACKGROUND: Aortopulmonary window is a rare conotruncal defect that is often associated with other congenital heart defects. We present a patient with a previously unreported combination of aortopulmonary window with tetralogy of Fallot with an absent conal septum. CASE PRESENTATION: A term, 2.4 kg newborn male infant presented at a community hospital with cyanosis unresponsive to supplemental oxygen. Transthoracic echocardiography demonstrated a conotruncal defect with a large conoventricular ventricular septal defect and an over-riding, dysplastic aortic valve. The main pulmonary artery (MPA) appeared to arise from left facing sinus of the aortic valve, with confluent yet hypoplastic right and left branch pulmonary arteries. There was no evidence of prograde flow into the MPA in systole, though there did appear to be retrograde flow in diastole from the patent ductus. The patient underwent multiple advanced imaging studies, and the diagnosis was not fully elucidated. Postmortem examination demonstrated morphology consistent with Tetralogy of Fallot with the absence of the conal septum. There were two distinct semilunar valves in fibrous continuity with an aortopulmonary window immediately cephalad to the valve. DISCUSSION: The rare combination of defects and the patient's size made the anatomic diagnosis by conventional imaging challenging. However, retrospective review of imaging studies did demonstrate anatomic features seen by direct examination of the specimen.

Metastatic Cardiac Angiosarcoma to the Lung, Spine, and Brain: A Case Report and Review of the Literature.

BACKGROUND: Metastatic angiosarcoma to the brain is a rare entity without an established management protocol. CASE DESCRIPTION: A man with primary cardiac angiosarcoma presented with a rare brain metastasis. The patient underwent successful resection of the brain metastasis and was initiated on chemotherapy only for his systemic disease. The patient did not develop local recurrence. A review of primary and metastatic central nervous system angiosarcoma, its pathologic features, clinical disease course, treatment strategies, and genomics is also provided. CONCLUSIONS: Angiosarcomas are rare tumors that are difficult to treat. Gross total resection of a central nervous system metastasis is recommended before initiation of adjuvant chemotherapy or radiation therapy. Close follow-up is still required given the propensity for continued metastasis of these tumors. Future treatments may be developed based on the genomics of angiosarcomas.

Hyaline droplets in Kupffer cells: a novel diagnostic clue for autoimmune hepatitis.

Pediatric autoimmune hepatitis (AIH) is relatively common and has a characteristic but relatively nonspecific histopathology with a usually prominent lymphoplasmacytic infiltrate. Herein, we describe for the first time the presence of characteristic hyaline droplets in the cytoplasm of Kupffer cells on routine hematoxylin and eosin (H&E) sections in AIH. The medical records and pathologic material over a 20-year period (1992 to 2012) were reviewed from children with AIH (n=30), hepatitis B virus (n=30), and hepatitis C virus (n=30) from the pathology files at Boston Children's Hospital. All children had percutaneous needle liver biopsies. We reviewed sections stained with H&E, PAS, and PAS with diastase for the presence of hyaline droplets in all 90 biopsies. We also performed immunohistochemical analysis for IgG, IgA, and IgD in 6 biopsies with AIH. Hyaline droplets were identified in Kupffer cells throughout the lobules in 15 of 30 biopsies (easily found in 13 and rare in 2); conversely, no droplets were identified in 15. Droplets were identified in 10 AIH type 1 biopsies, 1 in AIH type 2, 3 in overlap syndrome, and 1 in unclassified. Serum IgG levels, when available, were correlated with biopsy findings. Seventeen patients had serum IgG levels available for review. The average IgG level in patients without droplets in their biopsies was 1364 mg/dL, in contrast to 3424 mg/dL in patients with droplets (P=0.021). Immunohistochemical analysis performed in 6 biopsies revealed that droplets were nearly always positive for IgG, occasionally for IgA, and rarely for IgD. None of the biopsies in patients with hepatitis C contained hyaline droplets. One biopsy of a patient with hepatitis B revealed hyaline droplets; this biopsy had an unusually prominent plasmacytic infiltrate, and the patient was found to have an elevated IgG serum level and antibodies to smooth muscle actin. As far as we are aware, hyaline droplets in Kupffer cells on routine H&E sections have never been described. They should be distinguished from the nonspecific granular lysosomal structures frequently found in Kupffer cells in a variety of chronic liver diseases and from erythrophagocytosis. Hyaline droplets may occur in AIH regardless of the type and correlate with a >2-fold increase in serum level of IgG as compared with patients without droplets in their biopsies. Identification of hyaline droplets in Kupffer cells provides a useful diagnostic clue to distinguish AIH from other forms of chronic hepatitis.

Embryonal (undifferentiated) sarcoma of the liver with peripheral angiosarcoma differentiation arising in a mesenchymal hamartoma in an adult patient.

Embryonal (undifferentiated) sarcoma of the liver (ESL) is a rare malignant neoplasm composed of undifferentiated sarcomatous tissue. We are presenting a case of a 74-year-old woman diagnosed with an ESL arising from a mesenchymal hamartoma of the liver (MHL). Both lesions occur typically in childhood, with only rare reported cases in adults. Histologically, the mass consisted primarily of loose myxoid stroma admixed with bland spindle cells and extensive, cystic (lymphangioma-like) degeneration. However, also present peripherally were markedly atypical cells (including multi-nucleated forms) and hyaline globules. Additionally, atypical cells with a sinusoid tectorial growth pattern were identified, which were positive for CD31, CD34 and Factor VIII. The tumor cells of ESL are classically described as being negative for tissue-specific immunohistochemical markers. However our case demonstrated focal positivity for vascular markers CD31, CD34 and Factor VIII and this along with the sinusoidal tectorial growth pattern, mimicked an angiosarcoma.